Elucidating novel dysfunctional pathways in Alzheimer's disease by integrating loci identified in genetic and epigenetic studies

AbstractAlzheimer's disease is a complex neurodegenerative disorder. A large number of genome-wide association studies have been performed, which have been supplemented more recently by the first epigenome-wide association studies, leading to the identification of a number of novel loci altered in disease. Twin studies have shown monozygotic twin discordance for Alzheimer's disease (Gatz et al., 2006), leading to the conclusion that a combination of genetic and epigenetic mechanisms is likely to be involved in disease etiology (Lunnon & Mill, 2013). This review focuses on identifying overlapping pathways between published genome-wide association studies and epigenome-wide association studies, highlighting dysfunctional synaptic, lipid metabolism, plasma membrane/cytoskeleton, mitochondrial, and immune cell activation pathways. Identifying common pathways altered in genetic and epigenetic studies will aid our understanding of disease mechanisms and identify potential novel targets for pharmacological intervention

Library

This history for the Library was collected to commemorate DMACC\u27s 50th anniversary celebration during the 2015-16 academic year

Special Education in Juvenile Residential Facilities: Can Animals Help?

Children with emotional/behavioral disorders (EBD) are arguably one of the highest at-risk groups for dropping out before graduating high school. They are the group of students with disabilities who are most likely to be educated in residential facilities. Residential facilities such as Green Chimneys have incorporated animals into the treatment milieu with success. Animals have been used in various settings to improve the quality of life as well as the emotional and physical needs of people served by these facilities. This article describes the requirements for using animals in residential treatment, the limitations of such programs, and the research findings for the use of animal-assisted therapy or activities (AAT/AAA). Using Gardner’s (1999) iteration of his theory of multiple intelligence, the authors proposed an understanding of how these treatments might be improve the intelligence of a child with EBD. Requirements for effective treatment of special needs children were discussed

A Scale-Explicit Framework for Conceptualizing the Environmental Impacts of Agricultural Land Use Changes

Demand for locally-produced food is growing in areas outside traditionally dominant agricultural regions due to concerns over food safety, quality, and sovereignty; rural livelihoods; and environmental integrity. Strategies for meeting this demand rely upon agricultural land use change, in various forms of either intensification or extensification (converting non-agricultural land, including native landforms, to agricultural use). The nature and extent of the impacts of these changes on non-food-provisioning ecosystem services are determined by a complex suite of scale-dependent interactions among farming practices, site-specific characteristics, and the ecosystem services under consideration. Ecosystem modeling strategies which honor such complexity are often impenetrable by non-experts, resulting in a prevalent conceptual gap between ecosystem sciences and the field of sustainable agriculture. Referencing heavily forested New England as an example, we present a conceptual framework designed to synthesize and convey understanding of the scale- and landscape-dependent nature of the relationship between agriculture and various ecosystem services. By accounting for the total impact of multiple disturbances across a landscape while considering the effects of scale, the framework is intended to stimulate and support the collaborative efforts of land managers, scientists, citizen stakeholders, and policy makers as they address the challenges of expanding local agriculture

Choices in vaccine trial design in epidemics of emerging infections.

In a Policy Forum, Marc Lipsitch and colleagues discuss trial design issues in infectious disease outbreaks

Increased DNA methylation near TREM2 is consistently seen in the superior temporal gyrus in Alzheimer's disease brain

Although mutations within the TREM2 gene have been robustly associated with Alzheimer's disease, it is not known whether alterations in the regulation of this gene are also involved in pathogenesis. Here, we present data demonstrating increased DNA methylation in the superior temporal gyrus in Alzheimer's disease brain at a CpG site located 289 bp upstream of the transcription start site of the TREM2 gene in 3 independent study cohorts using 2 different technologies (Illumina Infinium 450K methylation beadchip and pyrosequencing). A meta-analysis across all 3 cohorts reveals consistent AD-associated hypermethylation (p = 3.47E-08). This study highlights that extending genetic studies of TREM2 in AD to investigate epigenetic changes may nominate additional mechanisms by which disruption to this gene increases risk

Evaluating the feasibility of delivering a pain management programme for adults living with sickle cell disease

Background Pain is the prominent feature of sickle cell disease (SCD) and negatively affects quality of life. Delivery of pain management programmes (PMPs) has been suggested in clinical guidelines for pain management in SCD; however, further evidence of the feasibility and effectiveness of PMPs in this population is needed. This study explored the feasibility of delivering a sickle cell pain management programme (SCPMP) for adults within a haemoglobinopathies service. Methods A single arm, repeated-measures observational design was used to determine feasibility of delivering the SCPMP at one study site. Primary feasibility outcomes were recruitment, completion of treatment and outcome measures, satisfaction, credibility and acceptability to participants. Secondary feasibility outcomes were treatment outcomes and processes, frequency of vaso-occlusive crisis (VOC) and healthcare utilisation. Results Four of five feasibility criteria were met. Annual recruitment of eight participants to a SCPMP was not achieved. Twenty-nine people began a SCPMP during the study period. Twenty-five (86.2%) participants attended ≥5/8 sessions and 21(84%) programme completers provided all end of programme questionnaires. Mean scores of >7 on ten-point scales were seen across satisfaction and credibility questions. At least moderate (Hedges g >0.5) effect sizes were seen in pre-post SCPMP measures of pain interference, anxiety, depression, self-efficacy, pain-related worry and acceptance. A small (Hedges g 0.4) effect size was seen in HRQoL. Following SCPMP attendance, mean frequency of self-reported VOC and hospital admissions reduced. Conclusions This study suggests that, given an adequate source of referrals, a SCPMP is feasible to deliver and appears acceptable and credible to participants. Exploration of influences on recruitment, such as barriers to group interventions, would be illuminating, prior to investigating feasibility of an adequately powered randomised-controlled trial

Lower Postsurgical Mortality for Individuals with Dementia with Better-Educated Hospital Workforce

Surgical patients age 65 and over with Alzheimer’s disease and related dementias (ADRD) were more likely to die within 30 days of admission and to die after a complication than those without ADRD. Having better-educated nurses in the hospital improved the likelihood of good outcomes for all surgical patients, but had a much greater effect in individuals with ADRD. Specifically, a 10% increase in the proportion of nurses with a Bachelor of Science in Nursing (BSN) degree or higher was associated with 10% lower odds of death and 10% lower odds of dying after a complication for surgical patients with ADRD

Bias modelling in evidence synthesis

Policy decisions often require synthesis of evidence from multiple sources, and the source studies typically vary in rigour and in relevance to the target question. We present simple methods of allowing for differences in rigour (or lack of internal bias) and relevance (or lack of external bias) in evidence synthesis. The methods are developed in the context of reanalysing a UK National Institute for Clinical Excellence technology appraisal in antenatal care, which includes eight comparative studies. Many were historically controlled, only one was a randomized trial and doses, populations and outcomes varied between studies and differed from the target UK setting. Using elicited opinion, we construct prior distributions to represent the biases in each study and perform a bias-adjusted meta-analysis. Adjustment had the effect of shifting the combined estimate away from the null by approximately 10%, and the variance of the combined estimate was almost tripled. Our generic bias modelling approach allows decisions to be based on all available evidence, with less rigorous or less relevant studies downweighted by using computationally simple methods

Pathogenic CD8 T Cells in Multiple Sclerosis and Its Experimental Models

A growing body of evidence suggests that autoreactive CD8 T cells contribute to the disease process in multiple sclerosis (MS). Lymphocytes in MS plaques are biased toward the CD8 lineage, and MS patients harbor CD8 T cells specific for multiple central nervous system (CNS) antigens. Currently, there are relatively few experimental model systems available to study these pathogenic CD8 T cells in vivo. However, the few studies that have been done characterizing the mechanisms used by CD8 T cells to induce CNS autoimmunity indicate that several of the paradigms of how CD4 T cells mediate CNS autoimmunity do not hold true for CD8 T cells or for patients with MS. Thus, myelin-specific CD4 T cells are likely to be one of several important mechanisms that drive CNS disease in MS patients. The focus of this review is to highlight the current models of pathogenic CNS-reactive CD8 T cells and the molecular mechanisms these lymphocytes use when causing CNS inflammation and damage. Understanding how CNS-reactive CD8 T cells escape tolerance induction and induce CNS autoimmunity is critical to our ability to propose and test new therapies for MS